CN102703060A - Targeted tracing noble metal fluorescence probe and anti-tumor prodrug - Google Patents
Targeted tracing noble metal fluorescence probe and anti-tumor prodrug Download PDFInfo
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Abstract
The invention relates to a bio-assay reagent for early diagnosis of tumor and a prodrug for the targeted therapy of tumor, in particular to a targeted tracing noble metal fluorescence probe and an anti-tumor prodrug. Through experiment, the synthesized probe does not have cytotoxicity and is safe and effective, can realize the level imaging of cells and the imaging of in-vivo tumor, and has good prospect when used as the targeted fluorescence probe or the prodrug.
Description
Technical field
The present invention relates to early diagnosis of tumor live body detection reagent and neoplasm targeted therapy prodrug.Be specifically related to target near infrared fluorescent probe and prodrug.
Background technology
Tumour is the major disease that threatens human health at present.The mortality ratio that malignant tumour causes is only second to cardiovascular disorder, is becoming human first killer, and human beings'health and existence in serious harm.Its sickness rate can be in any more always, and has presented tangible rejuvenation trend at present, and the annual newly-increased tumour patient in single inland of China reaches 2,000,000 people unexpectedly.Therefore, the diagnosis of raising cancer and curative ratio are the important means that improves human health and life quality.
At present, the conventional means that is used for diagnosing tumor is computer tomography (CT), MRI (MRI), ultrasonic (US) etc.Yet, the prerequisite that this type technology is used for diagnosing tumor be the volume growth of noumenal tumour to certain size, this has just brought limitation for early diagnosis of tumor.The technology that is used for function of organization's type detection that latest developments are got up comprises
18The scanning of F-deoxyglucose positron emission tomography (
18FDG-PET), single photon emission computed tomography (SPECT) can be used for the early diagnosis of tumour.Yet limited spatial resolution, high cost and high professional operative technique require to have hindered this type of broad application.Therefore, but a kind of complementary technique means of development is to realize the only way which must be passed of infantile tumour diagnosis at present.The method of current treatment tumour mainly contains radiotherapy, chemotherapy, operative therapy and gene therapy.Radiation and chemotherapy is very important non-operative treatment, but radiation and chemotherapy also produces major injury to organism normal cell in the kill tumor cell.Especially chemotherapy because medicine shortage target property itself, thereby occur that curative ratio is low, great treatment problem such as multidrug resistance, toxic side effect are huge.Therefore, the specificity of raising antitumor drug is the most important thing in the problem that needs to be resolved hurrily in the present chemotherapy.
Fluorescence nano bunch (NCs) is the research bright spot in the gold nano-material in recent years.NCs is piled up by dozens of to hundreds of gold atoms and forms, and size is less than 2 nanometers.Because the size of NCs approaches Fermi's wavelength rank (< 1nm) of electronics; Therefore with the surface plasma body resonant vibration of nanoparticle or nanometer rod cause to visible and the scattering of light of near-infrared band specific wavelength with absorb differently, the fluorescence nano cocooning tool has stronger fluorescent characteristic (400nm-750nm).2002, reports such as Link S adopted Peng Qinghuana and gsh reduction method to prepare Au NCs, its fluorescence quantum yield～10
-3(Link S, Beeby A, FitzGerald S, El-Sayed M, Schaaff T, Whetten R.Phys.J.Chem.B.2002,106:3410-3415.).Xie J etc. utilizes BSA to synthesize Au NCs as reductive agent and stablizer, its quantum yield be increased to 6% (Xie J, Zheng Y and Ying J Y.J.Am.Chem.Soc.2009,131:888-889.).Compare with traditional organic fluorescent dye, the fluorescence of NCs has the advantage that stability is high, the Stoke displacement is big; Compare with the inorganic fluorescent probe-quantum dot that has excellent fluorescent characteristic equally, the bio-toxicity of Au NCs is much lower; Simultaneously, the surface stabilizer of NCs is bioactive molecules (BSA, DNA, a polypeptide etc.), has given Au NCs and other bioactive molecule further link coupled ability.
Folic acid is VB11, and it is to get in the cell through folacin receptor (FR) mediated endocytosis picked-up folic acid and verivate thereof at the organism transporting pathway.FR is the membrane glycoprotein that a kind of glycosylation PI connects, the overexpression on the kinds of tumor cells surface, like ovarian cancer, cervical cancer, kidney etc., and in healthy tissues low expression level.At present, multinomial research confirms that folic acid can be used as a kind of targeting substance, and medicine or detection imaging substance are carried to tumor locus, plays magnetic target therapy and localized effect.2-amino-2-deoxy-D-glucose (2-DG) is a glucalogue, is indispensable energy derive in the metabolic process.Even malignant tumour also shows high glycolysis-rate and high glucose demand under aerobic conditions, accomplish picked-up to glucose through glucose transporter (GLUT1).Research shows that 2-DG can and be transported on the cytolemma by the phosphorylation of 2-deoxidation-6-phosphohexokinase by GLUT1 identification.Because 2 of 2-DG lack hydroxyl, thereby suppress the 2-deoxyglucose further metabolism of 6-phosphoric acid and in cell, keep.Because GLUT1 presents high expression level and high reactivity at tumor locus, therefore utilize 2-DG can effectively realize specific recognition to tumour as the cancer target part.2-DG has stability preferably in vivo, compares with the labelled with radioisotope imaging, in long-time imaging, has more advantage.At present, 2-DG fluorescence analogue can be used as the non-invasive probe of the novel medicine of accurate detection in organism to tumor efficiency.O ' Neil (O ' Neil RG, Wu L, Mullani N.Mol.Imag.Biol.2005; 7 (6): 388-392.) and Lloyd (Lloyd PG, Hardin CD, Sturek M.Physiol.Res.1999; 48 (6): 401-410.) synthesized 2-(N-7-nitrobenz2 OXA-1,3 diaxol-4-yls) amino]-2-deoxyglucose (2-NBDG), and pass through this compound of MCF-7 human breast cancer cell confirmation mainly through the absorption of GLUT HK approach.Opening and wait the people to synthesize burnt pheophorbide derivatize 2-DG, is a tumor-targeting near infrared fluorescent probe, can be used as treatment reagent (the Zhang M in the PDT again; Zhang Z, Blessington D, Li H; Busch TM, Madrak V.Bioconjug.Chem.2003; 14 (4): 709-714.).Journeys etc. confirm that with fluorescence microscopy the 2-DG of Cy5.5 dyestuff covalent coupling can have certain affinity (Cheng Z, Levi J, Xiong Z with the different cells strain; Gheysens O; Keren S, Chen X, Gambhir SS.Bioconjug.Chem.2006; 17 (3): 662-669.).Recently; Kovar etc. confirm that through the tumour nude mice model near infrared fluorescent dye (IRDye800) coupling 2-DG is an interior optical imaging agents of the body that extensively is suitable for and has done at the intravital tumor imaging of mouse (Kovar JL; Volcheck W; Sevick-Muraca E, Simpson MA, Olive DM.Anal.Biochem.2009; 384 (2): 254 – 262.).
Heptamethine cyanines dyestuff, near infrared acenaphthenequinone fluorochrome all are verivates of indoles dark green (ICG).Its emission wavelength is 700～1200nm; In this scope the biomolecules autofluorescence a little less than; Can avoid background interference and obtain higher sensitivity for analysis. and near-infrared fluorescent has stronger penetrance, can observe the information in body tissue deep through the near-infrared fluorescent imaging.Near the IR fluorescence dyestuff, help realizing in vivo real-time, on the throne, the nondestructive testing of bio signal at different nano materials, medicine, bioactive molecules cochain.
At present, to carry out that probe or medicine cancer target characteristic investigate be the fluorescent probe that needs coupling different to the live body level in most of cell in vitro levels and body, and this brings a lot of inconvenience to practical application.With 2-DG coupling near infrared fluorescent dye, can carry out real time imagery like Guo etc., and the mark that in cell levels is investigated, has further carried out the visible waveband fluorescent probe is beneficial to Fluirescence observation (Guo J at live body; Du C, Shan L, Zhu H; Xue B, Qian Z, Achilefu S; Gu Y.Contrast.Media.Mol.Imaging.2012,7 (3): 289-301.).Because cell levels and animal level have been investigated different probes, do not have consistence to a certain extent and increased the complicacy of method.The fluorogold nano-cluster (Au-BSA) of synthetic bovine serum albumin finishing such as Xu, owing to lack targeted molecular, it is longer that Au-BSA is targeted to time of tumor locus; Contrast gradient not high (Wu X, He X, the Wang K of while tumor locus and other tissue sites; Xie C; Zhou BQing Z.Nanoscale.2010,2,2244-2249).
In the present invention; Select precious metal fluorescence nano bunch fluorescent probe for use as visible waveband; Further coupling target property molecule (raising tumour-specific) and near infrared organic fluorescent dye; Obtain a kind of cell levels that not only can be used for and investigate but also can carry out the real-time spike of live body, have the multi-functional fluorescent probe of cancer target characteristic simultaneously; In addition, antitumor drug and the tumor-targeting molecule link coupled precious metal fluorescence nano of selecting to contain amino or carboxyl bunch carries out covalently bound, obtains a kind of anti-tumor predrug with tumour-specific.Fluorescent probe multiple characteristic (visible waveband fluorescence, near-infrared band fluorescence and tumour-specific) had both been given in this invention, had expanded the Application Areas (diagnosing tumor and oncotherapy) of fluorescent probe again, had application prospect.
Summary of the invention
The invention discloses traceable precious metal fluorescent probe and anti-tumor predrug with target characteristic.Compare with the conventional fluorescent probe, the present invention produces has high tumor-targeting, can realize the spike on the throne of cell levels and live body level simultaneously; This product can be used for the early diagnosis of tumour, simplifies experimental arrangement, reduces the experimental error that produces when using different fluorescent probe.Simultaneously,, can make the chemotherapeutics of no target property have target property, reduce toxic side effect, the curative ratio that improves tumour is had very important significance with the further covalently bound antitumor drug of target property molecule coupling precious metal fluorescent probe.Institute of the present invention synthetic probe is through experiment proof no cytotoxicity, and is safe and effective, both can realize the cell levels imaging, can realize the vivo tumor imaging again, as a kind of novel targeted fluorescent probe or prodrug good prospect arranged.
The traceable noble metal fluorescent probe of target characteristic of the present invention is made up of through covalent coupling noble metal nano-cluster, target property molecule and near infrared organic fluorescent dye, and its structure is seen Fig. 1.
The wherein preferred gold nano of heavy metal nano-cluster bunch, silver-colored nano-cluster, platinum nano-cluster or copper nano-cluster.
Target property molecule preferred antibody, folic acid, polypeptide, first sulphamide or 2-deoxyglucose.Preferred target property molecule is the 2-deoxyglucose.
Preferred Heptamethine cyanines dyestuff of near infrared organic fluorescent dye or near infrared acenaphthenequinone fluorochrome.
Near infrared organic fluorescent dye more preferably indoles flower cyanines is green, and structural formula is following:
The green structural formula of indoles flower cyanines
The invention also discloses a kind of antineoplastic target prodrug, constitute by noble metal nano bunch, target property molecule and tumor chemotherapeutic drug covalent attachment.The cancer therapy drug that wherein contains amino or carboxyl in the preferred chemical structural formula of tumor chemotherapeutic drug.Tumor chemotherapeutic drug is epirubicin, MTC or Dx more preferably.
The traceable noble metal fluorescent probe of target characteristic of the present invention can also connect antineoplastic chemotherapy medicine, is used for monitoring in real time and diagnosing tumor in the body of antineoplastic chemotherapy medicine, treatment.
The preferred epirubicin of antineoplastic chemotherapy medicine, MTC or Dx.
The traceable noble metal near infrared fluorescent probe of target characteristic of the present invention and the preferred 3:1～20:1 of antineoplastic chemotherapy medicine mol ratio.
Near infrared fluorescent probe of the present invention can be used following method preparation (so that gold nano bunch-2-amino-2-deoxy-D-glucose-indoles flower cyanines green (Au-2DG-MPA) be example): get gold nano bunch solution (Au NCs) and reach (3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) both mix the lucifuge stirring reaction; Add N-maloyl imines (NHS) after after reaction for some time again and continue the lucifuge stirring reaction; Reaction times is unsuitable long, adds 2-DG lucifuge stirring reaction then and spends the night.Product A u-2DG through the polydextran gel column purification, is removed unreacted raw material.Get organic nir dye MPA and with its activation.Get good Au-2DG solution of purifying and the good MPA solution of activation, mixing lucifuge stirring reaction spends the night, and behind the polydextran gel purifying, is final product Au-2DG-MPA again.
The present invention connects near infrared fluorescent dye and gives the ability of probe in the near-infrared fluorescent imaging on the basis of visible light wave range probe coupling target property molecule, can carry out cell research at visible waveband simultaneously, can carry out viviperception at near-infrared band again.The design of this probe has solved the problem that viviperception in cell in vitro research and the body needs different probe, and the present invention only can carry out cell research and the interior viviperception of body with a probe, simplification experimental arrangement and the experimental error that produces when changing probe.Synthetic probe Au-2DG-MPA of the present invention (the fluorogold nano-cluster Au NCs of covalent coupling 2-DG is not as negative control) and breast cancer cell MCF-7 hatched clean repeatedly 3 times with phosphate buffered saline buffer after 3 hours, utilize the laser co-focusing fluorescent microscope to gather the red fluorescence signal of gold nano bunch.The result shows that synthetic probe of the present invention and tumour cell have good affinity, in 3 hours time, passes cytolemma morely and enters into kytoplasm, and the faint (see figure 4) of the fluorescent signal of Au NCs in cell.This experimental result has confirmed that 2-DG is covalently coupled to AuNCs as the target part, can increase the fluorescence nano bunch affinity to tumour cell; Simultaneously also confirmed and to have detected probe of the present invention from cell levels.Synthetic probe Au-2DG-MPA of the present invention is arrived in the tumour nude mice model (mammary cancer MDA-MB-231) through tail vein injection, and at different time points (5min, 30min, 1h; 4h, 22h, 24h; 28h, 46h 53h) carries out the collection of near-infrared fluorescent image to nude mice model.The result shows that this probe can be targeted to tumor locus about 4h, and the fluorescent signal of other internal organs fades away in 72h after this, and the tumor locus fluorescent signal keeps higher SNR (see figure 5) always.Compare with other tumor-targeting fluorescent probe of having reported, like (Lingling Shan, Jianpeng Xue, Jing Guo et al.Bioconjugate Chemistry.2011,4,20 such as Shan; 22 (4): the folic acid that 567-581) uses connects nir dye as targeted molecular then needed 8 hours just can be targeted to knub position, but probe of the present invention only need 4 hours just target in clinical application, have more potentiality to tumor locus.
Through the fluorescence nano of covalent coupling target part bunch is carried out further activation, can covalently boundly go up and contain carboxyl or amino antitumor drug in the chemical structure.For example, the further activation of Au-2DG, (DOX) is connected with Dx, can obtain prodrug gold nano bunch-2DG-Dx (Au-2DG-DOX), sees shown in Figure 2.In order to confirm the tumour-specific of this prodrug, Au-2DG-DOX and DOX were hatched 1 hour with liver cancer cell 7402 respectively, carry out the IMAQ (see figure 7) through the laser co-focusing fluorescent microscope after cleaning three times repeatedly with phosphate buffered saline buffer again.The result shows, compares with DOX, and prodrug Au-2DG-DOX has higher avidity to liver cancer cell, enters into the quantity showed increased of cell cytosol, nucleus.The result of this result and above-mentioned Fig. 5 matches, and has further confirmed can strengthen its tumour-specific with behind probe or the last target part of medicine connection.
In sum, product of the present invention makes cell in vitro experiment and experiment made on the living can realize through same probe through coupling target part and near infrared fluorescent dye on fluorescence nano bunch; The near infrared fluorescent probe that the selected target of the present invention is ligand modified, it is shorter to arrive the required time of tumor locus than the tumor-targeting fluorescent probe of having reported.The anti-tumor predrug that obtains through further coupling antitumor drug behind the fluorescence nano bunch coupling target part can initiatively be targeted to tumor locus, and the drug level of tumor locus is significantly improved, and reduces the toxicity of medicine to healthy tissues.
Description of drawings
Fig. 1 is the Au-2DG-MPA structure iron
Fig. 2 is the Au-2DG-DOX structure iron
Fig. 3 is absorption spectrum and the fluorescence spectrum of Au-2DG-MPA.
Fig. 4 is that the acute toxicity investigation of Au-2DG-MPA obtains tissue slice figure.
Fig. 5 is Au-2DG-MPA and the Au NCs investigation to tumour cell MCF-7 affinity.
Fig. 6 is the Real-time and Dynamic distribution plan of Au-2DG-MPA in MDA-MB-231 tumour nude mice model.
Fig. 7 is that Au-2DG-DOX and DOX are the investigation of (7402) affinity to tumor cell of liver.
Embodiment
Embodiment 1
The preparation of Au NCs-2DG-MPA:
Get gold nano bunch solution 1ml; 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) 11.5mg, both mix the lucifuge stirring reaction, add N-maloyl imines (NHS) behind the 10min again and continue the lucifuge stirring reaction; Reaction times is unsuitable long, the EDC facile hydrolysis.React adding 2-DG 24mg after 2 hours, the lucifuge stirring reaction spends the night.Clarifying red tan solution (Au-2-DG) through sephadex column (G-25) purifying, is removed unreacted raw material.Get organic nir dye MPA 1mg, NSC 57182 (DCC), N-maloyl imines (NHS) lucifuge stirring reaction 3 hours.Get the good MPA solution 200 μ l of good Au-2DG solution 1ml of purifying and activation, mixing lucifuge stirring reaction 12 hours behind polydextran gel (G-25) purifying, is final product again.
Its absorption spectrum and fluorescence spectrum are seen Fig. 3.
The preparation of Au NCs-FA-MPA:
Get 22mg folic acid, 12mg1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (DCC), both mix the lucifuge stirring reaction N-maloyl imines (NHS), and the reaction times is unsuitable long, the EDC facile hydrolysis.React adding FA 24mg after 3 hours, the lucifuge stirring reaction spends the night.Clarifying red tan solution (Au-FA) through sephadex column (G-25) purifying, is removed unreacted raw material.Get organic nir dye MPA1mg, NSC 57182 (DCC), N-maloyl imines (NHS) lucifuge stirring reaction 3 hours.Get the good Au-FA solution 1ml of purifying, the MPA solution 200 μ l that activation is good, mixing lucifuge stirring reaction spends the night, and behind polydextran gel (G-25) purifying, is final product again.
Embodiment 3
The preparation of Au NCs-2-DG-DOX:
Get gold nano bunch solution 1ml; 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) 11.5mg, both mix the lucifuge stirring reaction, add N-maloyl imines (NHS) behind the 10min again and continue the lucifuge stirring reaction; Reaction times is unsuitable long, the EDC facile hydrolysis.React and add methionine(Met) (also claiming methionine(Met)) 15mg after 2 hours, the lucifuge stirring reaction spends the night.Clarifying red tan solution (Au-Met) through sephadex column (G-25) purifying, is removed unreacted raw material.Get organic nir dye DOX 1mg, NSC 57182 (DCC), N-maloyl imines (NHS) lucifuge stirring reaction 3 hours.Get the good Au-2-DG solution 1ml of purifying, the DOX solution 200 μ l that activation is good, mixing lucifuge stirring reaction spends the night, and behind polydextran gel (G-25) purifying, is final product again.
Claims (9)
1. near infrared namo fluorescence probe is characterized in that: be made up of through covalent coupling noble metal nano bunch, target property molecule and near infrared organic fluorescent dye.
2. the near infrared namo fluorescence probe of claim 1, wherein noble metal nano bunch is gold nano bunch, silver-colored nano-cluster, platinum nano-cluster or copper nano-cluster.
3. the near infrared namo fluorescence probe of claim 1, wherein target property molecule is antibody, folic acid, polypeptide, first sulphamide or 2-deoxyglucose.
4. the near infrared namo fluorescence probe of claim 1, wherein target property molecule is the 2-deoxyglucose.
5. the near infrared namo fluorescence probe of claim 1, wherein the near infrared organic fluorescent dye is Heptamethine cyanines dyestuff or near infrared acenaphthenequinone fluorochrome.
6. the near infrared namo fluorescence probe of claim 1, wherein the near infrared organic fluorescent dye is that indoles flower cyanines are green.
7. an antineoplastic target prodrug is characterized in that being made up of the near infrared namo fluorescence probe and the tumor chemotherapeutic drug covalent attachment of claim 1.
8. the cancer target prodrug of claim 7, wherein tumor chemotherapeutic drug is the cancer therapy drug that contains amino or carboxyl in the chemical structural formula.
9. the antineoplastic target prodrug of claim 7, wherein tumor chemotherapeutic drug is epirubicin, MTC or Dx.
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| CN106467743A (en) * | 2016-09-18 | 2017-03-01 | 东南大学 | Gold nanoclusters of high temperature resistant luminescence enhancement and its preparation method and application |
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| CN109266333A (en) * | 2018-10-23 | 2019-01-25 | 山西大学 | A kind of preparation method and application of Fluorescent silver nanocluster probe |
| CN112986561A (en) * | 2021-02-26 | 2021-06-18 | 福建师范大学 | Multimode immune instant analysis excited by nano titanium carbide hybrid |
| CN112986561B (en) * | 2021-02-26 | 2022-08-30 | 福建师范大学 | Multimode immune instant analysis excited by nano titanium carbide hybrid |
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